Tetrahydronaphthyloxy-aminopropanols and salts thereof

ABSTRACT

This invention relates to new tetrahydronaphthyloxy-aminopropanols and related compounds of the formula  AND TO SALTS OF SUCH COMPOUNDS, WHICH ARE USEFUL IN CORONARY DISEASES.

This application is a continuation-in-part of application Ser. No.48,458, filed June 22, 1970, and now abandoned.

This invention relates to new chemical compounds of the formula ##SPC2##

And salts of such compounds, wherein one or both of Z and Z¹ is hydroxyand/or OR" and the other (where necessary) can be hydrogen, or Z and Z¹taken together can represent O< , the radical ##EQU1## is a basicnitrogen containing radical of up to about 18 carbon atoms, R"represents an acyl group, R³, R⁴, R⁵, R⁶ and R⁷ are the same ordifferent and can be hydrogen or lower alkyl, R⁸, R⁹ and R¹⁰ are thesame or different and can be hydrogen, lower alkyl, monocyclic arylloweralkyl, lower alkoxy, carboxy, and monocyclic cycloalkyl.

The term "lower alkyl" as employed herein includes both straight andbranched chain radicals of up to and including eight carbon atoms, forinstance, methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl and the like.

The monocyclic aryl-lower alkyl groups include benzyl, phenethyl and thelike.

The term "lower alkoxy" includes straight and branched chain radicals ofthe structure RO- wherein R includes any of the above lower alkylgroups.

The "amino" groups include unsubstituted amino or mono- or di-loweralkyl-amino groups, wherein lower alkyl is as defined above, such asamino, methyl amino, ethyl amino, isopropyl amino, heptylamino, dimethylamino, diethyl amino, methyl ethyl amino, methyl butyl amino, ethyli-propyl amino and the like.

The acyl radicals represented by R" include lower fatty acid radicalssuch as acetyl, propionyl, butyryl, isobutyryl and the like, as well aslong chain fatty acid radicals such as hexanoyl, heptanoyl, decanoyl,dodecanoyl and the like, monocyclic aryl and aralkanoic acid radicalssuch as benzoyl, phenacetyl and the like.

The term "monocyclic aryl" as employed herein contemplates monocycliccarbocyclic aryl radicals, for instance, phenyl and substituted phenylradicals, such as lower alkyl phenyl (e.g., o-, m- or p-tolyl,ethylphenyl, butylphenyl and the like, di(lower alkyl)phenyl (e.g.,2,4-dimethylphenyl, 3,5-diethylphenyl and the like) halophenyl (e.g.,chlorophenyl, bromophenyl, iodophenyl, fluorophenyl), o-, m- orp-nitrophenyl, dinitrophenyl, (e.g., 3,5-dinitrophenyl,2,6-dinitrophenyl and the like), and trinitrophenyl (e.g., picryl).

The expression "monocyclic cycloalkyl" includes cyclic radicalscontaining from 3 to 6 ring members (e.g., cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl).

In the basic nitrogen containing radical ##EQU2## in formula I, R¹ andR² each represents hydrogen, lower alkyl, lower alkenyl, hydroxy-loweralkyl and phenyl-lower alkyl forming such basic groups as amino, loweralkylamino, e.g., methylamino, ethylamino, isopropylamino, di(loweralkyl)amino, e.g., dimethylamino, diethylamino, dipropylamino, loweralkenylamino, e.g., allylamino, di(lower alkenyl)amino, e.g.,diallylamino, (hydroxy-lower alkyl)amino, e.g., hydroxyethylamino,di(hydroxy-lower alkyl)amino, e.g., di(hydroxyethyl)amino, phenyl(loweralkyl)amino, e.g., benzylamino, phenethylamino, N-(loweralkyl)phenyl(lower alkyl)amino, e.g., N-methylbenzylamino, and the like.The ##EQU3## radical may form a heterocyclic radical. The symbols R¹ andR² may together represent the carbon (and hydrogen) and the oxygen,sulfur or nitrogen atoms which, with the nitrogen or carbon atom in theabove group, form a 5- or 6-membered nitrogen heterocyclic containingnot more than one hetero atom in addition to the nitrogen already shownin the group and less than 21 atoms in the radical (excluding hydrogen).The heterocyclic radicals may include one to three substituentsincluding lower alkoxy or lower alkyl as defined hereinbefore;trifluoromethoxy; trifluoromethylmercapto; N,N-dialkylsulfamoyl groups,such as N,N-dimethylsulfamoyl; lower alkanoyl groups ##EQU4## where R islower alkyl) as defined hereinbefore, such as acetyl, propionyl, and thelike; hydroxy-lower alkyl, such as hydroxymethyl,1-hydroxyethyl or thelike; hydroxy-lower alkoxy-lower alkyl, such as2-(2-hydroxy-ethoxy)ethyl, or the like; lower alkanoyl-lower alkyl, suchas 2-heptanoyloxyethyl; carbo-lower alkoxy, such as carbomethoxy,carboethoxy, carbopropoxy, or the like; or 2-(lower alkanoyloxy-loweralkaoxy)lower alkyl such as 2-(decanoyloxyethoxy)ethyl, or the like.

Illustrative of the heterocyclic radicals represented by ##EQU5## arethe following: piperidino; (lower alkyl)piperidino [e.g., 2-, 3-, or4-(lower alkyl)piperidino or 4-(N-lower alkyl)piperidino, such as2-(ethyl)piperidino or 4-(N-isopropyl)piperidino]; di(loweralkyl)piperidino [e.g., 2,4-, 2,5- or 3,5-di(lower alkyl)piperidino,such as 2,4-dimethyl piperidino or 2,5-di-t-butyl piperidino]; (loweralkoxy)piperidino [e.g., 2-methoxypiperidino or 3-methoxypiperidino];hydroxypiperidino [e.g., 3-hydroxy- or 4-hydroxypiperidino];aminomethylpiperidino [e.g., 4-aminomethylpiperidino]; pyrrolidino;(lower alkyl)pyrrolidino [e.g., 3-methylpyrrolidino]; di(loweralkyl)pyrrolidino [e.g., 3,4-dimethylpyrrolidino]; (loweralkoxy)pyrrolidino [e.g., 2-methoxypyrrolidino]; morpholino; (loweralkyl)morpholino [e.g., 3-methylmorpholino]; di(lower alkyl)morpholino,[e.g., 3,5-dimethylmorpholino]; (lower alkoxy)morpholino, [e.g.,2-methoxymorpholino]; thiamorpholino; (lower alkyl)thiamorpholino [e.g.,3-methylthiamorpholino]; di(lower alkyl)thiamorpholino, [e.g.,3,5-dimethylthiamorpholino], (lower alkoxy)thiamorpholino, [e.g.,3-methoxythiamorpholino]; piperazino; (lower alkyl)piperazino, [e.g., N⁴-methylpiperazino]; di(lower alkyl)piperazino, [e.g.,2,5-dimethylpiperazino or 2,6-dimethylpiperazino]; (loweralkoxy)piperazino, [e.g., 2-methoxypiperazino]; (hydroxy-loweralkyl)piperazino, [e.g., N⁴ -(2-hydroxyethyl)piperazino]; (loweralkanoyloxy-lower alkyl)piperazino, [e.g., N⁴-(2-heptanoyloxyethyl)piperazino or N⁴-(2-propionyloxyethyl)piperazino]; (hydroxy-lower alkoxy-loweralkyl)piperazino, [e.g., (hydroxymethoxymethyl)piperazino]; (carbo-loweralkoxy)piperazino, [e.g., N⁴ -(carbomethoxy-, carboethoxy-, orcarbopropoxy)piperazino]; piperidyl; (lower alkyl)piperidyl [e.g., 1-,2-, 3- or 4-(lower alkyl)piperidyl, such as 1-N-methylpiperidyl or3-ethylpiperidyl]; di(lower alkyl)piperidyl, [e.g., 2,4-, 2,5-, or3,5-di(lower alkyl)piperidyl wherein lower alkyl is methyl, ethyl,n-propyl, isopropyl, etc.]; lower alkoxy piperidyl, [e.g.,3-methoxypiperidyl or 2-ethoxypiperidyl]; hydroxypiperidyl [e.g.,3-hydroxy- or 4-hydroxypiperidyl]; aminomethylpiperidyl, [e.g.,4-aminoethylpiperidyl]; pyrrolidyl; lower alkyl pyrrolidyl, [e.g.,1-N-methylpyrrolidyl]; di(lower alkyl)pyrrolidyl, [e.g.,2,3-dimethylpyrrolidyl]; lower alkoxy pyrrolidyl, [e.g.,4-N-methoxypyrrolidyl]; morpholinyl; (lower alkyl)morpholinyl, [e.g.,3-methylmorpholinyl]; di(lower alkyl)morpholinyl, [e.g.,3-methyl-4-N-ethylmorpholinyl]; (lower alkoxy)morpholinyl, [e.g.,2-ethoxymorpholinyl]; thiamorpholinyl; (lower alkyl)thiamorpholino,[e.g., 3-ethylthiamorpholinyl]; di(lower alkyl)thiamorpholinyl, [e.g.,3-methyl-4-N-ethylthiamorpholinyl]; lower alkoxy thiamorpholino, [e.g.,3-methoxythiamorpholinyl]; piperazinyl; alkyl, dialkyl, alkoxy orhydroxy-lower alkyl substituted piperazinyl.

The compounds of formula I form acid addition salts with inorganic andorganic acids. These acid addition salts frequently provide useful meansfor isolating the products from reaction mixtures by forming the salt ina medium in which it is insoluble. The free base may then be obtained byneutralization, e.g., with a base such as sodium hydroxide. Then anyother salt may again be formed from the free base and the appropriateinorganic or organic acid. Illustrative are the hydrohalides, especiallythe hydrochloride and hydrobromide which are peferred, sulfate, nitrate,phosphate, borate, acetate, oxalate, tartrate, maleate, citrate,succinate, benzoate, ascorbate, salicylate, methanesulfonate,benzenesulfonate, toluenesulfonate and the like. Quaternary ammoniumsalts are also formed, e.g., by reacting the free base with analkylating agent, e.g., lower alkyl halide such as methyl chloride,ethyl bromide or the like, lower alkyl sulfate such as methyl sulfate,aralkyl halides such as benzyl chloride, aralkyl sulfates such as benzylsulfate and the like.

Preferred are those compounds wherein R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰are all hydrogen, R¹ is hydrogen or lower alkyl, especially hydrogen andR² is lower alkyl, especially isopropyl.

The compounds of this invention are useful as antifibrillatory agents,for example, in arresting cardiac arrhythmia in mammals, e.g., byinhibition of beta adrenergic receptors in the myocardium. For thispurpose a compound of formula I or a physiologically acceptable acidaddition salt may be incorporated in a conventional dosage form such astablet, capsule, elixir, injectable or the like along with the necessarycarrier material, excipient, lubricant, buffer or the like. Single ordivided doses of about 5 to 25 mg/kg, preferably about 4 to 10 mg/kg,two to four times daily may be administered in dosage forms as describedabove.

Examples of compounds falling within the present invention include, butare not limited to, the following: ##SPC3## ##SPC4## ##SPC5## ##SPC6####SPC7## ##SPC8## ##SPC9##

The compounds of formula I can be prepared by several methods.

In a first method for preparing compounds of formula I wherein one of Zand Z¹ is hydroxy and the other is hydrogen, a1-(5,8-dihydronaphthyloxy)-3-(substituted-amino)-2-propanol prepared asdescribed in copending application Ser. No. 768,176, filed Oct. 16,1968, issued Oct. 13, 1970, as U.S. Pat. No. 3,534,085, and having thestructure ##SPC10##

wherein R¹ through R¹⁰ are as defined hereinbefore, is reacted withdiborane or a mono- or dilower alkyl borane followed by an oxidativeworkup to give a mixture of alcohols of formula I wherein one Z and Z¹is hydroxyl and the other hydrogen. The mixture can then be separated bycolumn chromatography or fractional recrystallization of suitablederivatives such as the hydrochloride salt.

In another method for preparing compounds of formula I wherein Z and Z¹taken together are O< , or one of Z and Z¹ is hydroxy and the otherhydrogen, a naphthol of the structure ##SPC11##

is reduced with a metal like sodium or lithium in liquid ammoniacontaining an alkanol such as ethanol, isopropanol, t-butanol or thelike [e.g., by the procedure described in Organic Synthesis, Coll. Vol.4, page 887 (1963)] to obtain the 5,8-dihydronaphthol of the formula##SPC12##

The compound of formula IV is made to react with an epoxide of theformula ##EQU6## (Y is chlorine or bromine), to obtain a 1-(2,3-epoxypropoxy)-5,8-dihydronaphthalene of the formula ##SPC13##

The 1-(2,3-epoxy propoxy)-5,8-dihydronaphthalene is then coverted to thecorresponding1-[2,3-(epoxy)propoxy]-6,7-epoxy-5,6,7,8-tetrahydronaphthalene of thestructure ##SPC14##

by reacting the dihydronaphthalene (formula VI) in an inert solvent suchas methylene chloride (CH₂ Cl₂), with an organic peracid such asm-chloroperbenzoic acid, perbenzoic acid, pernitrobenzoic acid orperacetic acid. The tetrahydronaphthalent VII can be converted to thecorresponding 1-[(6,7-epoxy-5,6,7,8-tetrahydro-1-naphthyl)oxy]-3-(substitutedamino)-2-propanol of the structure ##SPC15##

by refluxing the tetrahydronaphthalene (formula VII) with an amine ofthe formula ##EQU7## in an inert organic solvent, such as n-propanol,benzene or toluene, e.g., for about 16 to 24 hours. An alternateprocedure involves heating the reactants in a Parr pressure reactor at atemperature within the range of from about 70° to about 110° for 6 - 12hours.

The 1-[6,7-epoxy-5,6,7,8-tetrahydro-1-naphthyl)-oxy]-3-(substitutedamino)-2-propanol VIII can be converted to the corresponding 6 or7-hydroxy compound of the structure ##SPC16##

wherein Z or Z¹ is hydroxy and the other is hydrogen by reduction with acomplex metal hydride such as lithium aluminum hydride or sodiumborohydride or catalytically over a noble metal catalyst such asplatinum oxide, followed by separation for example by chromatography.

1,2,3,4-Tetrahydro-5-[2-hydroxy-3-(substituted amino)propoxy]-2(or3)-naphthols of the structure X wherein one of Z and Z¹ is hydroxy andthe other is hydrogen can be prepared employing a 6 or7-methoxy-1-tetralone as the starting material, i.e., ##SPC17##

by reacting the 6 or 7-methoxy-1-tetralone with a dehydrogenating agentsuch as sulfur or palladium on charcoal at a temperature within therange of from about 240° to about 280°C. and preferably from about 245°to about 265°C., and then separating out, e.g., by chromatography, 6 or7-methoxy-1-naphthol of the structure ##SPC18##

The methoxy naphthol is then subjected to a Birch reduction wherein itis reacted with lithium in the presence of liquid ammonia to form5-hydroxy-3,4-dihydro-2(or 3) (1H)-naphthalenone after acidichydrolysis. ##SPC19##

The naphthalenone is reacted with a reducing agent, such as an alkalimetal borohydride, for example, sodium borohydride, in an alcoholsolvent, boiling below about 100°C., such as methanol, at a temperaturebelow about 100°C., and preferably below about 30°C.; acetic acid isadded to the reaction mixture and the solvent is removed to give5,6,7,8-tetrahydro-1,6 (or 7)-naphthalenediol ##SPC20##

The tetrahydronaphthalenediol is then converted to an alkali metal saltby mixing with an alkali metal alkoxide such as NaOCH₃ in an alcoholsolvent boiling below about 100°, such as methanol, and removing thesolvent in vacuo to give the dry salt which is reacted with an epoxideof formula V, such as epichlorohydrin in a solvent such asdimethylsulfoxide (as described herein) to form1,2,3,4-tetrahydro-5-[2,3-epoxy propoxy]-2 (or 3)-naphthol ##SPC21##

The above epoxy-propoxy-naphthol can be reacted with an amine ##EQU8##as described hereinbefore to form compounds of the invention of thestructure ##SPC22##

2,3-trans (or cis)-1,2,3,4-tetrahydro-5-[2-hydroxy-3-(substitutedamino)propoxy]-2,3-naphthalenediols of the structure ##SPC23##

can be prepared by forming a 5,8-dihydronaphthol of the structure##SPC24##

as described hereinbefore and dissolving the 5,8-dihydronaphthol inacetic anhydride and an organic base such as pyridine to form thecorresponding acetate of the structure ##SPC25##

The 2,3-trans isomer is prepared from the acetate by dissolving theacetate in acetic acid, and then treating the solution with from about 2to about 4 equivalents of silver acetate and from about 1 to about 2equivalents of iodine. The mixture is then heated at a temperature offrom about 80° to about 120°C for a period of from about 1 to about 24hours, under nitrogen, to thereby formtrans-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol of the structure XXVafter basic hydrolysis: ##SPC26##

The trans-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol can be converted tothe2,3-trans-1,2,3,4-tetrahydro-5-[2,3-(epoxy)-propoxy]-2,3-naphthalenediolof the structure ##SPC27##

by reacting the naphthalenetriol XXV with an alkali metal alkoxide, suchas sodium methoxide in an alcohol solvent boiling below about 100°C,such as methanol under nitrogen and then, after removal of solvent,stirring the residue in a dipolar aprotic solvent such asdimethylsulfoxide, hexamethylphosphoramide or dimethylformamide, and anepoxide of the structure V, such as epichlorohydrin, under nitrogen.

The2,3-trans-1,2,3,4-tetrahydro-5-[2,3(epoxy)-propoxy]-2,3-naphthalenediolis then reacted with a substituted amine of the structure ##EQU9## toform 2,3-trans-1,2,3,4-tetrahydro-5-[2-hydroxy-3-(substitutedamino)propoxy]-2,3-naphthalenediol of the structure ##SPC28##

The corresponding cis isomer of the structure ##SPC29##

can be prepared by dissolving the dihydronaphthalene acetate ##SPC30##

in acetic acid and water (from 92 to 98 % acetic acid, preferably 96%acetic acid), and then treating the solution with silver acetate andiodine and heating under nitrogen, as described in the preparation ofthe trans-isomer, to form thecis-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol after basic hydrolysis##SPC31##

which can be converted to the2,3-cis-1,2,3,4-tetrahydro-5-[2,3-(epoxy)-propoxy]-2,3-naphthalenediol,which in turn can be converted to the2,3-cis-1,2,3,4-tetrahydro-5-[2-hydroxy-3-(substitutedamino)propoxy]-2,3-naphthalenediol in a manner similar to that describedwith respect to the preparation of the corresponding trans isomer.

Alternatively, the2,3-trans-1,2,3,4-tetrahydro-5-[2-hydroxy-3-(substitutedamino)propoxy]-2,3-naphthalenediol isomer XXVII can be prepared from a5,8-dihydro-1-naphthol of the structure ##SPC32##

prepared as described hereinbefore, by mixing a cooled solution(temperature less than about 30°C.) of 5,8-dihydro-1-naphthol in ethylacetate with m-chloroperbenzoic acid and mixing the resulting slurrywith a mixture of ethyl ether and aqueous sodium bicarbonate, to form5,6,7,8-tetrahydro-6,7-epoxy-1-naphthol ##SPC33##

and reacting the 5,6,7,8-tetrahydro-6,7-epoxy-1-naphthol intetrahydrofuran with aqueous perchloric acid at a temperature within therange of from about 0° to about 60°C., to formtrans-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol XXV which can beconverted to the2,3-trans-1,2,3,4-tetrahydro-5-[2,3-(epoxy)propoxy]-2,3-naphthalenediolXXVI which in turn can be converted to the2,3-trans-1,2,3,4-tetrahydro-5-[2-hydroxy-3-(substitutedamino)propoxy]-2,3-naphthalenediol XXVII in a manner similar to thatdescribed hereinbefore.

A mixture of 1,2,3,4-tetrahydro-5-[2-hydroxy-3-(substitutedamino)-propoxy]-2-naphthol and the corresponding 3 -naphthol (formulaeXXI and XXII) can be prepared from5,6,7,8-tetrahydro-6,7-epoxy-1-naphthol (formula XXX) as follows.

The tetrahydro compound XXX is reduced to a mixture of the 2-naphtholXXI and the 3-naphthol XXII by reduction with a complex metal hydridesuch as lithium aluminum hydride or catalytically by hydrogen in thepresence of a noble metal catalyst as described hereinbefore, followedby conversion to the corresponding epoxides and then amino alcohols in amanner similar to that described hereinbefore.

Esters of the compounds of formula I, i.e., ##SPC34##

wherein one of Q and Q¹ is ##EQU10## wherein R¹² is lower alkyl, ormonocyclic aryl or lower alkyl-monocyclic aryl, and the other ishydrogen, can be prepared by reacting a compound of formula I whereinone of Z and Z¹ is hydroxy and the other hydrogen, with acetone or analdehyde of the structure XXXII ##EQU11## wherein R¹² is lower alkyl,monocyclic aryl or lower alkyl-monocyclic aryl in the presence of asolvent boiling below about 100°C., such as benzene or chloroform toform an oxazolidine compound of the structure ##SPC35##

and then reacting the oxazolidine with an acid anhydride or an acidhalide exemplified by the acids mentioned hereinbefore, in the presenceof a suitable base such as pyridine to give the ester of the oxazolidineof the structure ##SPC36##

Alternatively, the reaction product of the oxazolidine and the acidanhydride or halide can be reacted with phosgene to form a compound ofthe structure ##SPC37##

The oxazolidine compounds of XXXIV or XXXIVa can be converted to an acidaddition salt of formula I by acidic hydrolysis employing dilute aqueousacid as described hereinbefore, i.e.,

The following Examples further illustrate the invention.

EXAMPLE 11-[(6,7-Epoxy-5,6,7,8-tetrahydro-1-naphthyl)oxy]-3-(isopropylamino)-2-propanola. 2,3-Epoxypropyl 6,7-epoxy-5,6,7,8-tetrahydro-1-naphthyl ether

To a well-stirred solution of 7 g. (0.03 m.) of1-(2,3-epoxy-propoxy)-5,8-dihydro-naphthalene (prepared as described inapplication Ser. No. 768,176, filed Oct. 16, 1968, issued Oct. 13, 1970,as U.S. Pat. No. 3,534,085) in 60 ml. of CH₂ Cl₂, 7.1 g. (0.03 m.) of85% m-chloroperbenzoic acid in 100 ml. CH₂ Cl₂ is added dropwise at sucha rate that the temperature is maintained between 25° to 30° C. Themixture is stirred overnight at room temperature. The resultingprecipitate (m-chlorobenzoic acid) is filtered off and the CH₂ Cl₂extract is washed successively with sat. NaHCO₃ solution, and water.After drying (MgSO₄), the solution is evaporated in vacuo to give 7.2 g.(95%) of oil which solidifies. A sample recrystallized from ether giveswhite needles, m.p. 85°-87°; λ Nujol^(max) 1330-1350 cm⁻ ¹ (epoxy), τCDCl₃ absence of vinyl protons 4.0-4.2 region.

Anal. Calcd. for C₁₃ H₁₄ O₃ : C, 71.54; H, 6.47. Found: C, 71.50; H,6.77.

b.1-[(6,7-Epoxy-5,6,7,8-tetrahydro-1-naphthyl)oxy]-3-(isopropylamino)-2-propanol

A solution of 4.3 g. (0.02 m.) of2,3-epoxypropyl-6,7-epoxy-5,6,7,8-tetrahydro-1-naphthyl ether in 34 ml.(0.4 m.) of isopropyl amine is placed in a small Parr bomb and heated inan oil bath to approximately 70° to 80° (pressure gauge registered 50)for 10 hours. Evaporation of excess isopropyl amine in vacuo yields 5.3g. of a brown sticky solid. Crystallization from ether-pentane gives 2g. of off-white solid; m.p. 106°-110°. A second recrystallization fromether gives 0.6 g. of white solid as the first crop, m.p. 115°-117° C.,λ Nujol^(max), 3320 cm⁻ ¹ (NH), 1330-1350 cm⁻ ¹ (epoxy), TCDCl₃ 8.8 -9.0 [--CH(CH₃)₂ ].

Calcd. for C₁₆ H₂₃ NO₃ : C, 69.28; H, 8.36; N, 5.05. Found: C, 69.47; H,8.33; N, 5.09.

EXAMPLE 21,2,3,4-Tetrahydro-5-[2-hydroxy-3-(isopropylamino)propoxy]-2-naphtholand/or 1,2,3,4-tetrahydro-5-[2-hydroxy-3-(isopropylaminopropoxy]-3-naphthol

To a well-stirred slurry of 10 g. of lithium aluminum hydride in 250 ml.of ethyl ether is added dropwise a solution of 5.5 g. (0.02 m.) of2,3-epoxy-1,2,3,4-tetrahydro-5-[2-hydroxy-3-(isopropylamino)propoxy]naththalenein 100 ml. of dioxane. After heating under reflux for 12 hours, themixture is freed of excess hydride by the addition of aqueous potassiumcarbonate solution and filtered. Removal of solvent leaves a mixture ofalcohols which is taken up in benzene and chromatographed on 150 g. ofbasic alumina of Activity grade III. Elution with mixtures ofchloroform-methanol elutes the desired products. Seeding withcrystalline material (Example 3) induces crystallization of the2-isomer, and the 3-isomer (Example 7).

EXAMPLE 31,2,3,4-Tetrahydro-5-[2-hydroxy-3-(isopropylamine)-propoxy]-2-naphthol,oxalate salt (1:1) a. 6-Methoxy-1-naphthol

An intimate mixture of 81.5 g. (0.462 mole) of 6-methoxy-1-tetralone and14.5 g. (0.465 mole) of sulfur is heated at 240°-250° for 6 hours anddistilled to give 39.8 g. of oil, b.p. 158°-164° (0.3 - 0.5 mm.).Chromatography over Activity IV alumina followed by recrystallizationfrom 9:1 hexane-ethyl acetate gives 23.9 g. (29%) of6-methoxy-1-naphthol in 3 crops. m.p. 84°-86° (lit m.p. 84.5°-85°) Tet.,19 (12) 1919 (1963).

b. 5-Hydroxy-3,4-dihydro-2(1H)-naphthalenone

To a stirred slurry of 8.0 g. (0.048 mole) of 6-methoxy-1-naphthol and200 ml. of liquid ammonia held below the reflux temperature by externalcooling there is added 1.05 g. (0.15 g. - atom) of lithium ribbon over25 minutes. After a further 10 minutes at this temperature, 20 ml. ofethanol is added over 30 minutes. As the blue color fades, the ammoniais evaporated and the residue stirred overnight under nitrogen with 50ml. of water, 50 ml. of tetrahydrofuran and 35 ml. of conc. hydrochloricacid. Extraction with three 100 ml. portions of chloroform followed bydrying and solvent removal gives 7.24 g. of solid. Recrystallization(4:1) hexane-ethyl acetate gives 5.04 g. (68%) of ketone, m.p. 168°-171°(lit m.p. 155°-162° dec.), JACS 80, 2887 (1958).

c. 5,6,7,8-Tetrahydro-1,6-naphthalenediol

A 3.7 g. (0.0235 mole) sample of5-hydroxy-3,4-dihydro-2(1H)-naphthalenone in 125 ml. of methanol isadded to a cooled solution of 1.0 g. (0.025 mole) of sodium borohydridein 25 ml. of methanol. After 150 minutes at 0°, 7.2 g. of acetic acid isadded and the solvent removed in vacuo. Partitioning between water andmethylene chloride gives 3.54 g. of crude product after furtherextraction, drying and solvent removal. Recrystallization fromhexane-ethyl acetate gives 2.92 g., m.p. 126°-128.5°. (lit. m.p.127°-128°) JACS, 80, 2887 (1958).

d. 1,2,3,4-Tetrahydro-5-[2,3-epoxy-propoxy]-2-naphthol

A solution of 2.46 g. (0.015 mole) of5,6,7,8-tetrahydro-1,6-naphthalenediol and 810 mg. (0.015 mole) ofsodium methoxide in 30 ml. of methanol is prepared under nitrogen andthe solvent removed in vacuo. The resulting foam is stirred overnightwith 20 ml. of dimethylsulfoxide and 1.40 g. (0.015 mole) ofepichlorohydrin, poured into 200 ml. of water and extracted with four125 ml. portions of ether. Drying and solvent removal gives 3.06 g. ofoil which is purified by chromatography on silica gel (75 g.). Elutionwith hexane-chloroform mixtures gives a total of 1.56 g. (49%) ofmaterial with one spot on TLC.

e.1,2,3,4-Tetrahydro-5-[2-hydroxy-3-(isopropylamino)-propoxy]-2-naphthol

A solution of 1.50 g. of epoxide in 15 ml. of isopropylamine is heatedat 90° in a bomb for 8 hr. Solvent removal gives a solid which isrecrystallized from acetonitrile three times to give 1.21 g., m.p.136°-141°.

Anal. Calc'd for C₁₆ H₂₅ NO₃ : C, 68.78; H, 9.02; N, 5.0l Found: C,69.87; 69.61; H, 9.08; 9.17; N, 5.14; 5.09.

f.1,2,3,4-Tetrahydro-5-[2-hydroxy-3-(isopropylamino)-propoxy]-2-naphthol,oxalate salt

Conversion of1,2,3,4-tetrahydro-5-[2-hydroxy-3-(isopropylamino)-propoxy]-2-naphtholto its oxalic acid salt is accomplished by mixing equimolar amounts ofoxalic acid and amine in acetonitrile. The resulting solid isrecrystallized twice from ethanol to give 1.19 g., m.p. 163°-164.5°.

Anal. Calc'd for C₁₈ H₂₇ NO₇ : C, 58.52; H, 7.37; N, 3.79. Found: C,58.20; H, 7.30; N, 3.91.

EXAMPLE 42,3-trans-1,2,3,4-Tetrahydro-5-[2-hydroxy-3-(isopropylamino)propoxy]-2,3-naphthalenediola. 5,6,7,8-Tetrahydro-6,7-epoxy-1-naphthol

An amount of 25.0 g. (ca., 0.12 moles) of m-chloroperbenzoic acid isadded over 10 min. to an ice-cooled solution of 14.6 g. (0.10 mole) of5,8-dihydro-1-naphthol (prepared as described in Org. Syn., Coll. Vol.IV, pg. 887,) in 225 ml. of ethyl acetate. After 16 hr. at ambienttemperature the slurry is poured into a cooled, stirred mixture of 300ml. each of ether and 10% sodium bicarbonate. After 15 min. the organicphase is separated, washed with water, saturated salt solution anddried. Solvent removal gives an oil which is triturated with two 100 ml.portions of boiling hexane. The residue is recrystallized from 150 ml.of 1:1 hexane-ethyl acetate to give 6.6 g. (41%) of5,6,7,8-tetrahydro-6,7-epoxy-1-naphthol, m.p. 143°-146°. Two furtherrecrystallizations of a small sample give the analytical sample m.p.149.5°-151°.

Anal. Calc'd for C₁₀ H₁₀ O₂ : C, 74.05; H, 6.22; Found: C, 74.0l; H,6.21

b. trans-5,6,7,8-Tetrahydro-1,6,7-naphthalenetriol

A solution of 8.0 q. (0.048 mole) of5,6,7,8-tetrahydro-6,7-epoxy-1-naphthol in 100 ml. of tetrahydrofuran iscooled to 0° and 20 ml. of water and 0.5 ml. of 70% perchloric acid areadded. After 4 hrs., a further 1.5 ml. of acid is added and the solutionstirred for 16 hr. at ambient temperature and diluted with 100 ml. eachof ether, 10% sodium bicarbonate and saturated salt solution. Theaqueous layer is separated and washed with 150 ml. of 1:1ether-tetrahydrofuran. The organic phase is washed with saturated saltsolution, dried and evaporated to give an oil which solidifies ontrituration with chloroform. Recrystallization gives in two crops, 4.85g. of solid which is recrystallized from ethyl acetate to give 3.84 g.m.p. 179.5°-181.5°. Two further recrystallizations of a small samplegive the analytical specimen, m.p. 183°-184°.

Anal. Calc'd for C₁₀ H₁₂ O₃ : C, 66.65; H, 6.71; Found: C, 67.05; H,6.90.

c.2,3-trans-1,2,3,4-Tetrahydro-5-[2,3-(epoxy)-propoxy]-2,3-naphthalenediol

A solution of 3.60 g. of (0.02 mole) of5,6,7,8-tetrahydro-1,6,7-naphthalenetriol in 100 ml. of methanol iscooled to 0° to 1.08 g. (0.02 mole) of sodium methoxide in methanoladded. The solvent is removed in vacuo and the residue heated at 50° at0.05 mm. for 1 hr., dissolved in 80 ml. of dimethylsulfoxide and stirredovernight under nitrogen with 3.68 g. (0.04 mole) of epichlorohydrin.After 17 hr. the solvent is removed in vacuo, the residue dissolved in250 ml. of water and extracted 3 times with 150 ml. of ether and 2 timeswith 150 ml. of chloroform. Both organic extracts are washed with excess5% sodium hydroxide, saturated salt solution and dried. Solvent removalgives a total of 3.25 g. of solid which is recrystallized from benzeneto give 2.59 g., m.p. 113°-116°.

d.2,3-trans-1,2,3,4-Tetrahydro-5-[2-hydroxy-3-(isopropylamino)propoxy]-2,3-naphthalenediol

A solution of 2.5 g. (0.0106 mole) of2,3-trans-1,2,3,4-tetrahydro-5-[2,3-(epoxy)-propoxy]-2,3-naphthalenediolin 15 ml. of isopropyl amine is heated at 80° ± 5° for 16 hr. in a Parrbomb (pressure = 40 lb/in²). The solution is evaporated in vacuo to givea foam which crystallizes on trituration with ether. Filtration gives2.96 g. which is recrystallized three times from benzene to give 2.06g., m.p. 112°-127°.

Anal. Calc'd for C₁₆ H₂₅ NO₄ : C, 65.06; H, 8.53; N, 474. Found: C,65.35; H, 8.44; N, 4.61.

EXAMPLE 52,3-cis-1,2,3,4-Tetrahydro-5-[2-hydroxy-3-(isopropylamino)propoxy]-2,3-naphthalenediola. cis-5,6,7,8-Tetrahydro-1,6,7-naphthalenetriol

A solution of 29.2 g. (0.2 mole) of 5,8-dihydro-1-naphthol and 40 ml. ofacetic anhydride in 100 ml. of pyridine is prepared. After 16 hr. thesolvent is removed in vacuo and the residue dissolved in ether andwashed with 200 ml. of 5% hydrochloric acid, water, 200 ml. of 10%sodium hydroxide, saturated salt solution and dried. Solvent removalgives 34.2 g. (90.5%) of crude acetate which is dissolved in 900 ml. ofacetic acid and 36 ml. of water. 53.3 g. (0.32 mole) of silver acetateis added followed by 40.6 g. (0.16 g-atom) of iodine. The slurry isheated with good stirring at 85°± 10° for 3 hr. under nitrogen, cooledand filtered. The filtrate is evaporated in vacuo and the residuedissolved in 250 ml. of methanol and cooled to 0°. A solution of 40 g.of sodium hydroxide in 200 ml. of water is added under nitrogen and themixture stirred overnight. The bulk of the methanol is removed in vacuowhereupon a solid forms. The solid is separated by filtration, dissolvedin 150 ml. of water and acidified with 20 ml. of concentratedhydrochloric acid. Cooling gives a solid which is filtered and dried togive 16.5 g. 2,3 cis-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol) m.p.184.5°-187°. Three recrystallizations from absolute ethanol give theanalytical sample, m.p. 188°-188.5°.

Anal. Calc'd for C₁₀ H₁₂ O₃ : C, 66.65; H, 6.71 Found: C, 66.19; H,6.68.

b.2,3-cis-1,2,3,4-Tetrahydro-5-[2,3-(epoxy)-propoxy]-2,3-naphthalenediol

A solution of 1.20 g. (0.03 mole) of sodium methoxide and 5.4 g. (0.03mole) of cis-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol in 200 ml. ofmethanol is prepared under nitrogen. The residue obtained upon solventremoval is stirred overnight with 200 ml. of dimethylsulfoxide and 4.65g. (0.05 mole) of epichlorohydrin under nitrogen. The bulk of thesolvent is removed at 50° at 0.1 mm. and the residue dissolved in 500ml. of water. Extraction with chloroform (10 × 200 ml.) gives 3.46 g. ofsolid which is recrystallized from 150 ml. of hexane-ethyl acetate togive 2.80 g. of epoxy diol of the above title, m.p. 108°-111.5°.

c.2,3-cis-1,2,3,4-Tetrahydro-5-[2-hydroxy-3-(ispropylamino)propoxy]-2,3-naphthalenediol.

A solution of 2.75 g. (0.011 mole) of2,3-cis-1,2,3,4-tetrahydro-5-[2,3-(epoxy)-propoxy]-2,3-naphthalenediolin 20 ml. of isopropylamine is heated at 80° ± 5° in a Parr bomb (press.≈ 40 lb/in²) for 16 hr. The excess amine is removed in vacuo and theresidue recrystallized twice from 350 ml. of benzene to give 2.32 g.,m.p. 112°-120.5°.

Anal. Calc'd for C₁₆ H₂₅ NO₄ : C, 65.06; H, 8.53; N, 4.74 Found: C,65.27; H, 8.65; N, 4.61.

EXAMPLE 61,2,3,4-Tetrahydro-5-[2-hydroxy-3-(benzylisopropylamine)propoxy]-2(and3)-naphthol

A solution of 3.26 g. (0.0093 mole) of1-(5,8-dihydro-1-naphthyloxy)-3-(benzyl isopropylamino)-2-propanol(prepared as disclosed in application Ser. No. 768,176 issued Oct. 13,1970, as U.S. Pat. No. 3,534,085) in 25 ml. of dry tetrahydrofuran istreated dropwise with a solution of 0.1 mole of borane intetrahydrofuran. After stirring for 16 hours, the mixture is freed ofsolvent and the residue taken up in 25 ml. of 95% ethanol and treatedwith 0.8 g. (0.02 mole) of sodium hydroxide followed by dropwiseaddition of 2.5 ml. of 30% hydrogen peroxide (0.02 mole). After a 2 1/2hour period at reflux the mixture is taken to near dryness in vacuo andthe product extracted into ether. Chromatography on activity II neutralalumina affords the two isomeric alcohols of the above title.

EXAMPLE 71,2,3,4-Tetrahydro-5-[2-hydroxy-3-(isipropylamineo)-propoxy]-(isopropylamino)3-naphthol

Following the procedure described in Example 3, but substituting7-methoxy-1-tetralone for 6-methoxy-1-tetralone, the above titledcompound is prepared.

EXAMPLE 81,2,3,4-Tetrahydro-5-[2-hydroxy-3-(isopropylamino)-propoxy]2(and 3)naphthol a. 5,6,7,8-Tetrahydro-1,6 (and 7)naphthalenediol

To a well stirred suspension of 5 g. of lithium aluminum hydride in 100ml. of ether is added dropwise a solution of 8.0 g. (0.048 mole) of5,6,7,8-tetrahydro-6, 7-epoxy-1-naphthol in 100 ml. ether. After severalhours under reflux, the mixture is treated with aqueous acid, and theproducts isolated from the organic solvents.

b. 1,2,3,4-Tetrahydro-5-[2,3-(epoxy)-propoxy]-2(and 3) naphthol

A solution of 3.28 g. (0.02 mole) of the mixture of diols in 100 ml. ofmethanol is cooled to 0° and 1.08 g. (0.02 mole) of sodium methoxide inmethanol added. The solvent is removed in vacuo and the residue heatedat 50° under 0.05 mm. for 1 hour, dissolved in 80 ml. ofdimethylsulfoxide and stirred overnight under nitrogen with 3.68 g.(0.04 m.) of epichlorohydrin. After removal of solvent in vacuo, theresidue is dissolved in 250 ml. of water and extracted three times withchloroform. After washing with 5% sodium hydroxide and saturated saltsolution, solvent is removed to leave crude product recrystallized frombenzene-petroleum ether.

c. 1,2,3,4-Tetrahydro-5-[2-hydroxy-3-(isopropylamino)-propoxy]-2 (and 3)naphthol

A solution of 2.2 g. (0.01 mole) of1,2,3,4-tetrahydro-5-[2,3-(epoxy)-propoxy]-2 (and 3) naphthol in 15 ml.of isopropylamine is heated at 80° ± 5° for 16-20 hours in a Parr bomb.The cooled solution is taken to dryness and the residue crystallizedfrom benzene-petroleum ether to give the above titled mixture.

EXAMPLE 92-Acetoxy-1,2,3,4-tetrahydro-5-[(2-hydroxy-3-(isopropylamino)propoxy]naphthalenea. 3-Isopropyl-5-(5,6,7,8-tetrahydro-6-hydroxy-1-naphthoxy)methyloxazolidine hydrochloride

A solution of 5.58 g. (0.02 mole) of1,2,3,4-tetrahydro-5-[2-hydroxy-3-(isopropylamino)propoxy]-2-naphthol in30 ml. of 99% ethanol is treated with 4 ml. of 33% formalin and heatedunder reflux for 12-16 hours. The solution is acidified withhydrochloric acid in ethanol and the oxazolidine hydrochlorideprecipitated by the addition of ether.

b.2-Acetoxy-1,2,3,4-tetrahydro-5-[(2-hydroxy-3-(isopropylamino)propoxy]naphthalene

The oxazolidine hydrochloride is dissolved in dry pyridine and treatedwith 0.1 mole of acetic anhydride at room temperature. After severalhours standing, the mixture is poured into water and made acid withdilute hydrochloric acid. After stirring for several hours, the mixtureis basified with aqueous ammonia in the cold and the product isolated byextraction into chloroform, drying and solvent removal.

EXAMPLES 10 to 15

By substituting a 1-(2,3-epoxy-propoxy)-5,8-dihydro-naphthalene as shownin the left hand first column of Table I for the corresponding startingmaterial in Example 1a and employing the procedure of Example 1 a, a2,3-epoxypropyl-6,7-epoxy-5,6,7,8-tetrahydro-1-naphthyl ether is formed.By reacting the naphthyl ether with an amine of the structure ##EQU12##employing the procedure of Example 1 b, and thereafter reacting theresulting product (as shown in the middle column of Table I) with LiAlH₄employing the procedure of Example 2, the product shown in the righthand (third) column of Table I is produced.

                                      TABLE I                                     __________________________________________________________________________    Example                                                                           R.sup.3                                                                            R.sup.4                                                                          R.sup.5                                                                          R.sup.6                                                                           R.sup.7                                                                          R.sup.8                                                                             R.sup.9                                                                          R.sup.10                                                                         R.sup.3 to R.sup.10 same                                                                R.sup.1       R.sup.2                                               as in Col. 1                                __________________________________________________________________________    10   H   CH.sub.3                                                                         H  CH.sub.3                                                                          H  CH.sub.3                                                                            H  H  "         H             C.sub.4                                                                       H.sub.9             11   C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                  C.sub.2 H.sub.5                                                                  H   H  H     NH.sub.2                                                                         H  "         --(CH.sub.2).sub.2 OH                                                                       H                   12   C.sub.6 H.sub.13                                                                  H  CH.sub.3                                                                         H   H  CH.sub.3                                                                            CH.sub.3                                                                         H  "                       CH.sub.3            13   t-C.sub.4 H.sub.9                                                                 H  H  t-C.sub.4 H.sub.9                                                                 H  CH.sub.3                                                                            CH.sub.3                                                                         CH.sub.3                                                                         "         H             --NH                                                                          |                                                                    CH.sub.3            14   H   H  C.sub.3 H.sub.7                                                                  H   H  COOH  H  H  "         --N           NH                  15   H   H  H  H   H        H  H  "         --N           O                   Example                                                                            R.sup.1 to R.sup.10 same                                                                    Z        Z.sup.1                                                as in cols. 1                                                                 and 2                                                                    __________________________________________________________________________    10   "             OH       H                                                 11   "             H        OH                                                12   "             OH       --                                                13   "             --       OH                                                14   "             OH       --                                                15   "             --       OH                                                __________________________________________________________________________

EXAMPLES 16 - 21

Employing the procedure of Example 3 a, but substituting a6-alkoxy-1-tetralone as shown in the left hand (first) column of TableII for 6-methoxy-1-tetralone, a 6-alkoxy-1-naphthol is produced, whichis converted as per Example 3 b to the corresponding5-hydroxy-3,4-dihydro-2(1H)-naphthalenone shown in the middle column ofTable II; employing the procedure of Example 3 c the naphthalenone isconverted to the corresponding 5,6,7,8-tetrahydro-1,6-naphthalenediolwhich is reacted with an epoxide of the structure ##EQU13## inaccordance with the procedure of Example 3d to form the corresponding1,2,3,4-tetrahydro-5-[2,3-epoxy-propoxy]-2-naphthol which is reactedwith an amine of the structure ##EQU14## in accordance with theprocedure of Example 3e to form the corresponding1,2,3,4-tetrahydro-5-[2-hydroxy-3-(R¹, R² -substitutedamino)propoxy]-2-naphthol (formula I) as shown in the right hand (third)column of Table II.

                                      TABLE II                                    __________________________________________________________________________    Example                                                                            R.sup.12                                                                           R.sup.8                                                                            R.sup.9                                                                            R.sup.10                                                                           R.sup.8 - R.sup.10                                                            as in Col. 1                                         __________________________________________________________________________    16   C.sub.2 H.sub.5                                                                    H    CH.sub.3                                                                           H    41                                                   17   t-C.sub.4 H.sub.9                                                                  H    H    t-C.sub.4 H.sub.9                                                                  "                                                    18   i-C.sub.3 H.sub.7                                                                  C.sub.5 H.sub.11                                                                   H    H    "                                                    19   CH.sub.3                                                                           CH.sub.3 O                                                                         CH.sub.3                                                                           H    "                                                    20   C.sub.6 H.sub.13                                                                   C.sub.3 H.sub.7                                                                    H    COOH "                                                    21   C.sub.5 H.sub.11                                                                   H    H    NH.sub.2                                                                           "                                                    Example                                                                            R.sup.8 to R.sup.10 as                                                               R.sup.3                                                                            R.sup.4                                                                           R.sup.5                                                                           R.sup.6                                                                            R.sup.7                                                                           R.sup.1                                                                            R.sup.2                                     in Col. 1                                                                __________________________________________________________________________    16   "      H    H   H   C.sub.5 H.sub.11                                                                   CH.sub.3                                                                          H    H                                      17   "      i-C.sub.3 H.sub.7                                                                  H   C.sub.2 H.sub.5                                                                   H    H   H                                           18   "      C.sub.2 H.sub.5                                                                    CH.sub.3                                                                          H   H    H                                               19   "      H    H   H   C.sub.6 H.sub.13                                                                   H                                               20   "      H    H   H   H    CH.sub.3                                                                          CH.sub.3                                    21   "      H    CH.sub.3                                                                          H   CH.sub.3                                                                           H   CH.sub.3                                                                           CH.sub.3                               __________________________________________________________________________

EXAMPLES 22 to 27

Following the procedure of Example 4a but substituting the substituted5,8-dihydro-1-naphthol shown in the left hand most (first) column ofTable III for 5,8-dihydro-1-naphthol, the5,6,7,8-tetrahydro-6,7-epoxy-1-naphthol shown in the second column isformed. Following the procedure of Example 4b, the 1-naphthol in thesecond column is converted to the5,6,7,8-tetrahydro-1,6,7-naphthalenetriol set out in the third column ofTable III. The naphthalenetriol is then reacted with sodium methoxideand an epoxide of the structure ##EQU15## in accordance with theprocedure of Example 4c to form a2,3-trans-1,2,3,4-tetrahydro-5-[2,3-(epoxy)-propoxy]-2,3-naphthalenediolwhich is reacted with a R¹, R² -substituted amine in accordance with theprocedure of Example 1d to form the product shown in the right hand most(fourth) column of Table III.

    __________________________________________________________________________    Example                                                                            R.sup.8     R.sup.9                                                                           R.sup.10                                                                          R.sup.8 - R.sup.10                                                            same as in Col. 1                                    __________________________________________________________________________    22   COOH        H   H   "              "                                     23   H               H   "              "                                     24   H           H   NH.sub.2                                                                          "              "                                     25   C.sub.2 H.sub.5 O                                                                         H   CH.sub.3                                                                          "              "                                     26   CH.sub.3    CH.sub.3                                                                          CH.sub.3                                                                          "              "                                     27               H   H   "              "                                     Example                                                                            R.sup.8 -R.sup.10 same                                                                R.sup.1                                                                            R.sup.2                                                                            R.sup.3                                                                           R.sup.4                                                                            R.sup.5                                                                            R.sup.6                                                                           R.sup.7                                   as in Col. 1                                                             __________________________________________________________________________    22   "       --N  NH   H   CH.sub.3                                                                           H    H   H                                    23   "                 C.sub.2 H.sub.5                                                                   CH.sub.3                                                                           H    H   H                                    24   "       N    O    H   H    C.sub.6 H.sub.13                                                                   C.sub.2 H.sub.5                                                                   H                                    25   "                 H   i-C.sub.3 H.sub.7                                                                  CH.sub.3                                                                           H   H                                    26   "       CH.sub.3                                                                           CH.sub.3                                                                           H   H    C.sub.2 H.sub.5                                                                    H   H                                    27   "       H    H    H   H    H    CH.sub.3                                                                          CH.sub.3                             __________________________________________________________________________

EXAMPLES 28 to 33

Following the procedure of Example 5a, but substituting ##SPC38##

for the 5,8-dihydro-1-naphthol and reacting the above substitutednaphthol with a carboxylic acid anhydride ##EQU16## the compound shownin the left hand (first) column of Table IV is formed, which is reactedwith silver acetate and iodine as in Example 5a to form acis-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol as shown in the middlecolumn of Table IV. The triol is reacted with an epoxide of thestructure ##EQU17## as per Example 5b to form a2,3-cis-1,2,3,4-tetrahydro-5-[2,3-(epoxy)-propoxy]-2,3-naphthalenediolwhich is reacted with an R¹, R² -substituted amine in accordance withExample 5c to form the product shown in the right hand column of TableIV.

                                      TABLE IV                                    __________________________________________________________________________    Example                                                                            R.sup.12   R.sup.8                                                                           R.sup.9                                                                            R.sup.10                                                                          R.sup.8 - R.sup.10 same                                                       as in Col. 1                                     __________________________________________________________________________    28   CH.sub.3   COOH                                                                              H    H   "                                                29   C.sub.2 H.sub.5                                                                          NH.sub.2                                                                          H    H   "                                                30   C.sub.3 H.sub.7                                                                          H   CH.sub.3                                                                           CH.sub.3                                                                          "                                                31              H   C.sub.2 H.sub.5 O                                                                  H   "                                                32              H   H    H   "                                                33   C.sub.4 H.sub.9                                                                          CH.sub.3                                                                          C.sub.2 H.sub.5                                                                    CH.sub.3                                                                          "                                                Example                                                                            R.sup.8 - R.sup.10 same                                                                R.sup.1                                                                             R.sup.2                                                                            R.sup.3                                                                           R.sup.4                                                                           R.sup.5                                                                           R.sup.6                                                                           R.sup.7                                   as in Col. 1                                                             __________________________________________________________________________    28   "        CH.sub.3                                                                            C.sub.2 H.sub.5                                                                    H   H   CH.sub.3                                                                          H   CH.sub.3                             29   "        C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                    H   C.sub.2 H.sub.5                                                                   CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                             30   "        --N   NH   H   H   H   H   H                                    31   "        --NN--(CH.sub.2).sub.2 OH                                                                H   C.sub.6 H.sub.13                                                                  H   CH.sub.3                                                                          CH.sub.3                             32   "                   CH.sub.3                                                                          H   CH.sub.3                                                                          CH.sub.3                                                                          H                                    33   "        H     i-C.sub.3 H.sub.7                                                                  H   C.sub.3 H.sub.7                                                                   H   C.sub.2 H.sub.5                                                                   C.sub.4 H.sub.9                      __________________________________________________________________________

EXAMPLE 342,3-cis-1,2,3,4-Tetrahydro-5-[2-hydroxy-3-(tert-butylamino)propoxy]-2,3-naphthalenediola. cis-5,6,7,8-Tetrahydro-1,6,7-naphthalenetriol

A solution of 29.2 g. (0.2 mole) of 5,8-dihydro-1-naphthol and 40 ml. ofacetic anhydride in 100 ml. of pyridine is prepared. After 16 hr. thesolvent is removed in vacuo and the residue dissolved in ether andwashed with 200 ml. of 5% hydrochloric acid, water, 200 ml. of 10%sodium hydroxide, saturated salt solution and dried. Solvent removalgives 34.2 g. (90.5%) of crude acetate which is dissolved in 900 ml. ofacetic acid and 36 ml. of water. 53.3 g. (0.32 mole) of silver acetateis added followed by 40.6 g. (0.16 g-atom) of iodine. The slurry isheated with good stirring at 85° ± 10° for 3 hr. under nitrogen, cooledand filtered. The filtrate is evaporated in vacuo and the residuedissolved in 250 ml. of methanol and cooled to 0°. A solution of 40 g.of sodium hydroxide in 200 ml. of water is added under nitrogen and themixture stirred overnight. The bulk of the methanol is removed in vacuowhereupon a solid forms. The solid is separated by filtration, dissolvedin 150 ml. of water and acidified with 20 ml. of concentratedhydrochloric acid. Cooling gives a solid which is filtered and dried togive 16.5 g. cis-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol) m.p.184.5°-187°. Three recrystallizations from absolute ethanol give theanalytical sample, m.p. 188°-188.5°.

Anal. Calc'd for C₁₀ H₁₂ O₃ : C, 66.65; H, 6.71 Found: C, 66.19; H,6.68.

b.2,3-cis-1,2,3,4-Tetrahydro-5-[2,3-(epoxy)-propoxy]-2,3-naphthalenediol

A solution of 1.20 g. (0.03 mole) of sodium methoxide and 5.4 g. (0.03mole) of cis-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol in 200 ml. ofmethanol is prepared under nitrogen. The residue obtained upon solventremoval is stirred overnight with 200 ml. of dimethylsulfoxide and 4.65g. (0.05 mole) of epichlorohydrin under nitrogen. The bulk of thesolvent is removed at 50° at 0.1 mm. and the residue dissolved in 100ml. of water. Extraction with chloroform (10 × 200 ml.) gives a solidwhich is recrystallized from 150 ml. of hexane-ethyl acetate to giveepoxy diol of the above title.

c.2,3-cis-1,2,3,4-Tetrahydro-5-[2-hydroxy-3-(tert-butylamino)propoxy]-2,3-naphthalenediol

A mixture of 3.0 g. of2,3-cis-1,2,3,4-tetrahydro-5-[2,3-(epoxy)-propoxy]-2,3-naphthalenediol(m.p. 104°-107°, one spot on TLC--alumina, 5% methanol in chloroform,iodine visualization) and 22 ml of t-butyl amine is heated at 85°-95°for 15 hours in a Parr bomb and the excess amine removed in vacuo. Thesolid obtained by trituration of the residue with ether is filtered andrecrystallized from benzene to give 3.4 g., m.p. 124°-136°.

Anal. Calcd for C₁₇ H₂₇ NO₄ : C,65.99; H,8.80; N,4.53. Found: C,66.08;H,8.88; N,4.45.

What is claimed is:
 1. Compounds of the structure ##SPC39##andstereoisomers and salts thereof, wherein R¹ is lower alkyl; R³, R⁴, R⁵,R⁶ and R⁷ are the same or different and are selected from the groupconsisting of hydrogen and lower alkyl; and R⁸, R⁹ and R¹⁰ are the sameor different and are selected from the group consisting of hydrogen,lower alkyl, lower alkoxy and cycloalkyl.
 2. Compounds of the structure##SPC40##and stereoisomers and salts thereof, wherein R¹ is lower alkyl,and wherein the two adjacent hydroxy groups are in the cisconfiguration.
 3. The compound in accordance with claim 2 having thename2,3-cis-1,2,3,4-tetrahydro-5-[2-hydroxy-3-(isopropylamino)propoxy]-2,3-naphthalenediol.4. Compounds of the structure ##SPC41##stereoisomers thereof and saltsthereof.
 5. The compound in accordance with claim 4 having the name2,3-cis-1,2,3,4-tetrahydro-5-[2-hydroxy-3-(tert-butylamino)propoxy]-2,3-naphthalenediol.6. Compounds of the structure ##SPC42##and stereoisomers and saltsthereof, wherein R¹ is lower alkyl.
 7. Compounds of the structure##SPC43##and stereoisomers and salts thereof, wherein R¹ is lower alkyl.